Project Summary We recently discovered that commensal Neisseria kill Ngo through a novel mechanism that is based on genetic competence and DNA methylation state. Consistent with these in vitro findings, human commensal N. elongata (Nel) accelerates Ngo clearance from the mouse, and an Ngo DNA uptake mutant resists this clearance. We propose a model for how commensal Neisseria DNA kills Ngo. Based on these and other findings, we hypothesize that any DNA has the potential to kill Ngo, provided it is taken up into the cell and its methylation pattern is considered foreign to the pathogen. In this R21, we propose to this idea using in vitro approaches and the mouse model of Ngo lower genital tract infection. These studies allow us to assess the potential of DNA as an alternative gonococcal microbicide and shed light on a little understood facet of commensal Neisseria-pathogenic Neisseria interactions.